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Amyloid, ApoE4, and aging—each is infamous for raising the risk of Alzheimer’s disease. But dig deeper and we are foggy about whether, or how, each factor weakens memory in the cognitively healthy. The latest findings from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study take a step toward answering the question.

In the January 22 JAMA Neurology, researchers led by Paul Maruff, University of Melbourne, Australia, report that in people with brain amyloid, episodic memory dips below a normality threshold beginning at age 76. In ApoE carriers with brain amyloid, this starts a decade earlier. So far, this new data confirms what’s known. Surprisingly, however, people without brain amyloid remember just fine, even those who carry an ApoE4 allele. “This challenges the notion of age-related memory loss, as it is widely assumed that aging in and of itself plays a role in decline,” wrote first author Yen Ying Lim to Alzforum. Instead, it looks as if Aβ explains much of the variance in the memory decline seen in aging studies, Lim said.

This study gibes with others that are starting to show that cognitive function remains relatively stable over time when there is no amyloid (Lim et al., 2016; Jack et al., 2015).

To find out how amyloid, age, and ApoE interact, Lim and colleagues included 447 cognitively normal participants from AIBL in their analysis. They averaged 72.5 years old. The scientists genotyped them for ApoE, took their brain amyloid PET values at baseline, then divided the cohort into four groups depending on Aβ and ApoE4 status. On average, the amyloid-positive group was four years older than the amyloid-negative group. All participants took episodic memory tests every 18 months for six years, and the researchers combined results from the California Verbal Learning Test, the Logical Memory delayed recall test, and the Rey Complex Figure Test into a composite score.

Amyloid-positives were the only ones with any episodic memory loss. Their decline began, on average, around age 76. If a participant also carried an ApoE4 allele, his or her decline started nearly a decade earlier—at 65. By age 85, amyloid-positive ApoE4 carriers had fallen 1.5 standard deviation units below amyloid-negative noncarriers on the composite, characteristic of someone who has trouble recalling recently acquired memories and is approaching mild cognitive impairment, said Lim. Amyloid-positive noncarriers had fallen by 0.7 SDs at that age. By contrast, episodic memory held steady in people without plaques, regardless of their ApoE4 status.

The authors used a cross-sectional quadratic model to correlate age with change in episodic memory (see figure above). This explained the variance better than linear models that had been used in most other studies. The model suggests that memory decline in Aβ–positive people may accelerate with older age, and that this acceleration may be due to ApoE4, claim the authors.

The data confirm what shorter studies hinted at, namely that ApoE4 on its own does not drive risk of memory loss in cognitively healthy people (Mormino et al., 2014).

“The unique and valuable contribution of the AIBL study is the long clinical follow-up of participants, which strengthens confidence in conclusions about the relationships among amyloid, ApoE, and cognitive decline,” noted Clifford Jack from the Mayo Clinic in Rochester, Minnesota. He had suspected as much after analyzing data from longitudinal studies at the Mayo Clinic. “The main mechanism by which ApoE4 negatively affects cognition is mediated through amyloidosis,” he wrote to Alzforum.

“It is important to demonstrate this interplay between ApoE4 and amyloid,” Richard Caselli, Mayo Clinic, Phoenix, wrote to Alzforum. He had previously suggested that memory does take a hit in cognitively healthy ApoE4 carriers (Caselli et al., 2009). However, that study did not determine whether subjects had amyloid in the brain, and so couldn’t tell whether ApoE4 worked alone or through amyloid. “Considering the prevention trials underway that are based on ApoE genotype, this study reminds us that an amyloid-targeted intervention should be applied to those individuals whose brains harbor that target, i.e. amyloid, and that we cannot assume they do based on possession of an E4 allele,” he wrote, even though scientists know that does put them at greater risk.

Lim and colleagues do not report how ApoE4 affected amyloid accumulation in this study, but she told Alzforum they are analyzing that data. The paper suggests that if an ApoE4 carrier is amyloid-negative, then his or her memory will not decline for at least six years, the duration of serial measurement in this study. “The estimates provided may be used to determine the risk of memory decline associated with Aβ and ApoE4 at each age,” wrote the authors.

They note that since their sample comes from a selected, mostly college-educated population, excluding people with cardiovascular risk factors and other medical and psychiatric conditions, it needs to be repeated in a population-based sample. They also caution that they had too few ApoE4 homozygotes to learn what two copies of this allele do over time. Finally, since they just used baseline scans for this analysis, the authors did not calculate how memory decline correlated with the amount of accumulation, or how ApoE4 affected that accumulation. That analysis is to come.—Gwyneth Dickey Zakaib